Penile erection depends on the relaxation of cavernosal smooth muscle. Relaxation of the trabecular smooth muscle permits dilation of the lacunar spaces, causing engorgement of the penis. Inflow of blood at the systemic blood pressure to the lacunar spaces expands the relaxed trabeculae against the tunica albuginea. This compresses the subtunical venules, reduces venous outflow from the lacunar space, and elevates lacunar space pressure, making the penis rigid. Contraction of the cavernosal smooth muscle leads to penile detumescence. This results in a reduction of arterial inflow and a collapse of the lacunar spaces with decompression of subtunical venules and increased venous outflow from the lacunar spaces, returning the penis to the flaccid state.
Penile erectile dysfunction is a common medical disorder. It has been estimated that it is prevalent in 2% of men aged 40 years, which an increase to over 50% in men over the age of 70 years, affecting some 10 to 20 million men in the US alone. Intracavernosal injection of vasodilators, such as prostaglandin E1 (PGE1, alprostadil; CAVERJECT.TM./Upjohn-for intracavernosal use), is a commonly used treatment for erectile dysfunction (Porst, J. Urol. 155(1996)802-812). When injected into the penis, prostaglandin E1 can induce an erection within a few minutes in up to 80% of cases, and acts by relaxing the smooth muscle of the penis. Different formulations of prostaglandin E1 are now available and have been compared (Vanderschueren et al., J. Urol. 154(1995) 1744-1747). Mechanism and side effects have been studied (Granata et al., Psychosom. Med. 57 (1995) 336-344; Italiano et al., Pharmacol. Res. 31 (1995) 313-317). Although effective, the drawbacks of intracavernosal injection therapy include the inconvenience of injection, discomfort, stress and pain during injection and penile scarring (Gana et al., Curr. Ther. Res. 57 (1996) 700-710; Chen et al., J. Urol. 155 (1996) 138-140). As prostaglandins undergo first pass metabolism and adverse reactions such as diarrhea follow oral use, they cannot be administered orally.
Other methods for treating erectile dysfunction include malleable (bendable) or inflatable penile implants or prostheses, which are manufactured by several different companies. However, such devices require surgery. The use of penile suppositories, in which a drug is delivered transurethrally, (alprostadil in MUSE; medicated urethral system for erections), can be painful or less effective. Oral corporal pharmacotherapy also has been used. Apomorphine treatment, in which a pellet is placed under the tongue for absorption into the blood stream, works by stimulating receptors in the brain which may then result in an erection five to twenty minutes after administration. Sildenafil citrate (VIAGRA.TM., Pfizer) has become available more recently and has been shown to help about 70% of men with impotency problems. However, in patients with preexisting cardiovascular disease, there is a potential for cardiac risk of sexual activity associated with VIAGRA use. Further, patients taking any medicines that contain nitrates, which are often used as treatments for angina (chest pain due to heart disease), cannot take VIAGRA. Moreover, not all patients respond to VIAGRA treatment.
Topical/transdermal delivery of vasodilators that stimulate erectile function is another possibility for treating erectile dysfunction (e.g., hydralazine; U.S. Pat. No. 4,801,587). Transdermal delivery of prostaglandins has been shown to be feasible (Watkinson et al., Int. J. Pharm. 74 (1991) 229-236., Uekama et al., J. Pharm. Pharmacol. 44 (1992) 119-121), and delivery is facilitated by penetration enhancers. It has been shown that PGE1 permeated across hairless mouse skin in-vitro when delivered by iontophoresis, but not by passive transport (aqueous solution used; Saeki et al., Int. J. Pharm. Therapeutics 36 (1996) 525-529). However, the lag time of absorption may be too long for treatment of erectile disorders, as a response within 5-20 minutes is desired. When 500 microgram of PGE1 was applied to the genital area, immediate erection could not be obtained (Chiang et al., Ann. Acad. Med. Singapore 24 (1995) 767-769).
Thus, in view of the problems associated with current methods for treating erectile dysfunction by injectable and systemic pharmacotherapies and prostheses, a need exists for the development of alternative methods for treating erectile dysfunction. The present invention satisfies this need and provides related advantages as well.